1. Field of the Invention
The present invention relates to quinoline derivative fumarates having a stimulating activity on the carcinostatic effect. The present invention further relates to agents containing said fumarates which stimulate the carcinostatic effect of carcinostatic agents and to a method of stimulating the carcinostatic effect using said carcinostatic agents in combination. 2. Description of the related Art
The number of cancer patients worldwide has been increasing every year; in Japan, cancer has the highest mortality rate of all the cause of death, and social interest in cancer treatment, particularly in chemotherapy, is high. However, to date, an extremely small number of effective drugs has been developed for cancer treatment although extensive efforts have been made.
One of the greatest clinical problems with chemotherapy for cancer treatment is that cancer cells become resistant to various kinds of carcinostatic agents. That is, for example, cells which are resistant to adriamycin are resistant also to a number of other carcinostatic agents, which makes cancer treatment very difficult. This multi-drug resistance phenomenon is considered to be caused by a protein called glycoprotein P, which is expressed by cancer cells on the surface of the cells and stimulates extracellular excretion of carcinostatic agents.
Accordingly, it has been strongly desired to develope an agent having the following characteristics:
(a) It can interfere with the action of the glycoprotein P and provide a treatment of a cancer having such resistant by overcoming the drug resistance, i.e., it can strongly stimulate carcinostatic effects of caricinostatics. PA1 (b) It has no or substantially no toxicity for clinical use.
As a result of intensive studies and research under the above-mentioned circumstances, the present inventors found that specific compounds and their salts exhibit a strong action in stimulating carcinostatic effect on drug resistant cancer and have low toxicity and low side effects, which was reported in European Patent Publication No. 0363212 A2. The main compounds them are quinoline derivatives classified in a group of compounds which contain basic amines and are highly fat-soluble. These compounds can be clinically used in practice in a form of an agent for oral administration or for injection; however, these compounds have a disadvantage in oral absorbability or solubility in water because of a limitation in their physical properties. Accordingly, it has been desired to develop a novel compound having improved characteristics of high solubility in water and of sufficient oral absorbability, in which the above-mentioned physical properties are improved.